Tetrahydronaphthalene and indane compounds useful for reversing the photodamage in sun-exposed skin

ABSTRACT

The use of compounds of formula I as topical agents to combat the disorders of the skin produced by photodamage which disorders include: wrinklin, elastosis and premature aging is described. Compounds of formula I are ##STR1## wherein n represents 1 or 2, Z represents --S(O)R, wherein R represents lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl, lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino 
     and pharmaceutically acceptable salts thereof.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 07/219,615filed 7-14-87 abandoned which is a continuation-in-part of Ser. No.86,992 filed Aug. 19, 1987 now abandoned.

BACKGROUND OF THE INVENTION

The skin, particularly in humans, contains an elaborate network ofelastin fibers which are responsible for maintaining its elasticproperties. With excessive exposure to sunlight the elastic fiber systembecomes hyperplastic, disorganized and ultimately disrupted. This isknown as actinic elastosis and is the principal cause of wrinkling,discoloration and laxity of the skin in the exposed areas of the body.The skin can repair itself to some extent but it is neverthelessdesirable to have an agent which can accelerate the repair of thisprematurely aged skin.

The UVB irradiated hairless mouse has been found to be a convenientmodel for actinic elastosis in the skin. (Kligman et al. J. Invest.Dermatol. 78:181 (1982). It has been shown by Johnston et al. in J.Invest. Dermatol. 82:587 (1984) that irradiation with low levels of UVBwhich simulate realistic solar exposure leads to a significant increasein skin elastin as measured by desmosine content. The amount of thisamino acid, which is isolated from acid hydrolysis of elastin, isproportional to the elastin present in the skin. (Uitto et al., Lab.Invest. 49:1216 (1973). Treatment of irradiated mice with topicalretinoic acid has been shown to normalize the histological features ofthe skin in which the previously elastotic dermis has the appearance ofunirradiated tissue (Kligman et al., Conn. Tissue Res. 12:139 (1984),Kligman U.S. Pat. No. 4,603,146 July 1986). Therefore this model can beused to determine the efficacy of compounds in the repair of sum damagedskin.

SUMMARY OF THE INVENTION

In accordance with this invention, compounds of formula ##STR2##

wherein n represents 1 or 2; Z represents --S(O)R, wherein R representslower-alkyl, lower-alkenyl, lower alkynyl, lower-alkoxy-lower-alkyl,lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl,lower-carbalkoxy-lower-alkyl, lower-alkoxy, hydroxy, mono-lower-alkylamino or di-lower-alkylamino,

and pharmaceutically acceptable salts thereof applied topically to theskin of a patient reverses the conditions associated with photodamage.Hence, by the topical application of compounds of formula I to the skinof patients which has been damaged through sun exposure, the effects ofwrinkling, elastosis and premature aging can be reversed leading to animprovement in the appearance of the skin.

Through the topical administration of the compounds of the formula I,the acceleration of repair of dermal damage is accomplished so as toprovide the skin with a smoother and younger appearance.

DETAILED DESCRIPTION

The term "lower" as used herein denotes groups which preferably contain1-4 carbon atoms. Alkyl groups can be straight-chain or branched-chain.Preferred lower-alkyl groups are methyl, ethyl and isopropyl. Examplesof lower-alkenyl groups are vinyl, allyl and methallyl. Examples oflower-alkanoyl groups are acetyl, propionyl, and butyryl. Alkynyl groupscan be straight-chain or branched-chain. Preferred lower alkynyl groupsare ethynyl and propynyl. The term "halogen" embraces fluorine,chlorine, bromine and iodine, of which chlorine is preferred. Examplesof lower-carbalkoxy-lower-alkyl groups are carbomethoxy- andcarboethoxy-methyl and -ethyl. Examples of lower-alkoxy groups aremethoxy and ethoxy. Examples of alkylamino groups are methylamino,ethylamino, isopropylamino, dimethylamino and diethylamino.

The invention relates to tetrahydronaphthalene and indane compounds ofthe formula ##STR3##

wherein n represents 1 or 2; Z represents a group --S(O)R, wherein Rrepresents lower-alkyl, lower-alkenyl, lower alkynyl,lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl,hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl,lower-alkoxy, hydroxy, mono-lower-alkylamino or di-lower-alkyl-amino

and pharmaceutically acceptable salts thereof.

A pharmaceutically acceptable salt of compounds of formula I, whichcompounds belong to the class of retinoids, includes any salt chemicallypermissible in the art for compounds of formula I and applicable tohuman patients in a pharmaceutically acceptable preparation. Among suchpharmaceutically acceptable salts of compounds of formula I there areespecially included salts of sulfinic acids of compounds of formula I.Any conventional pharmaceutically acceptable base salt of sulfinic acidsof compounds of formula I can be utilized. Among the conventional basesalts which can be utilized there are included, for example, alkalimetal salts such as sodium or potassium, alkaline earth metal salts suchas calcium or magnesium, and ammonium or alkyl ammonium salts.Furthermore, conventional acid addition salts, such as acetates, may beutilized for compounds of formula I wherein R is mono- lower-alkylaminoor di-lower-alkyl-amino.

Of the compounds of formula I wherein Z represents --S(O)R, there arepreferred those compounds in which R is lower-alkyl, lower-alkenyl,hydroxy-lower-alkyl, lower-alkoxy, hydroxy, mono-lower-alkylamino ordi-lower-alkylamino.

Furthermore, there are especially preferred compounds of formula I inwhich R is lower-alkyl. Further preferred compounds of formula I arethose in which n of formula I is 2.

The following compounds of formula I are especially preferred:

ethylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfoxide;and

methylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfoxide.

Another interesting compound of the invention is ethylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfinate.

Processes for preparing compounds of Formula I are set forth in U.S.Pat. No. 4,396,553 which is hereby incorporated by reference.

The compounds of the formula I when applied topically to the skin,reverse the conditions associated with photodamage so as to moderate andretard the damage to the skin caused by sun exposure. The damage causedsun exposure may include premature aging, elastosis and wrinkling. Thisdamage is more pronounced in older patients. By applying the compoundsof formula I topically to the skin in an amount effective to reverse theconditions associated with photodamage, the acceleration of skin repairis accomplished to enhance the skin with a smoother and youngerappearance. The compounds of formula I should be applied to that portionor area of the skin which is affected by photodamage or in whichtreatment is desired. The use of the compounds of formula I inaccordance with this invention can provide the effects of anti-aging andanti-wrinkling, as well as enhance the repair of sun damaged skin.

A compound of formula I, or a combination of compounds of formula I canbe applied in accordance with this invention to human skin inconventional topical compositions. These compositions can be utilized toapply compounds of formula I to the skin of the body, particularly theface, legs, arms and hands. The preferred method of application ofcompounds of formula I topically to produce the best effects shouldstart where a patient is between 30 and 55 years of age, when elastosisbegins to appear and becomes more pronounced. Thereafter, thiscomposition can be continuously applied to patients to reduce theeffects and injury associated with sun exposure. Generally, it ispreferred to begin the treatment when the patient reaches approximately30 years of age and to continue the treatment throughout his life, inorder that the effects of elastosis be reduced and to prevent anyfurther progression of photodamage.

The compounds of formula I can be administered in accordance with thisinvention in any conventional suitable topical preparation, i.e. incombination with any suitable conventional carrier useful for topicaladministration. Therefore, compounds of formula I can be administered inaccordance with this invention in any suitable topical composition suchas a cream, ointment, soap, solution, lotion, emulsion, shampoo, etc.Generally, for most efficacious results, these topical compositionscontain from about 0.00001% to about 1.0% by weight of the totalcomposition of a compound of formula I, with amounts of from about0.0001% to about 0.1% by weight of the composition being especiallypreferred. If desired, higher concentrations may be utilized dependingupon the nature and extent of elastosis.

In formulating these compositions, any conventional non-toxic,dermatologically acceptable base or carrier in which a compound offormula I is stable can be utilized. The preferred compositions for usein this invention are the conventionally cosmetic compositions which cancontain a cosmetically active ingredient which is topically administeredto human skin to provide a cosmetic effect. Among the conventionalcosmetically active materials which can be utilized in this compositionare included: sunscreens, penetration enhancers, moisturizers,surfactants, emollients, colorants, conditioners, bacteriocides,astringents, detergents, etc.

The topical compositions of this invention can, if desired containsuitable sunscreen agents. Any conventional sunscreen agent can beutilized in formulating the formulations containing compounds of formulaI which can be utilized in accordance with this invention.

These topical compositions which contain compounds of formula I cancontain any of the conventional excipients and additives commonly usedin preparing topical compositions. Among the conventional additives orexcipients, which can be utilized in preparing these cosmeticcompositions in accordance with this invention are preservatives,thickeners, perfumes and the like. In addition, the conventionalantioxidants, such as butylated hydroxyanisoles (BHA), ascorbylpalmitate, propyl gallate, citric acid butylated hydroxy toluene (BHT),ethoxyquin, tocopherol, and the like can be incorporated into thesecompositions. These topical compositions can contain conventionalacceptable carriers for topical applications which are generallyutilized in these compositions. These compositions may containthickening agents, humectants, emulsifying agents and viscositystabilizers, such as those generally utilized. In addition, thesecompositions can contain flavoring agents, colorants, and perfume whichare conventional in preparing cosmetic compositions.

The topical compositions containing compounds of formula I can beapplied to the skin and should be preferably applied to the skin atleast once a day for at least 2 or 3 times a week. For obtaining thereversal of the elastosis so as to impart to the skin a smooth andyounger appearance the topical compositions should be preferably appliedfor a period of at least five months. After that compositions whichcontain compounds of formula I should be applied continually to maintainthe effect of younger and smoother skin. These preparations can beapplied according to the need of the patient as determined by theprescribing physician. In any event, the particular regimen forapplication of this composition to a patient will typically depend onthe age, weight and skin condition of the individual.

The invention is further illustrated in the following examples. Theseexamples are for illustration and are not limitative of the claimedinvention.

EXAMPLE 1 Repair of UVB-Induced Dermal Damage in the Hairless Mouse byCompounds of Formula I

Hairless mice (HRS/J strain, Jackson Labs, 5-7 weeks old at the start ofthe experiments) were irradiated three times per week with a bank of 8Westinghouse Sunlamps (FS40) placed about 20 cm above the animals. Theradiation dose was controlled by an International Light Model IL844APhototherapy Exposure Control and a detector. The UVB dosing schedulewas such that individual doses, seldom exceeding 0.06 J/cm², causedminimal erythema but no burning or scarring. There was significantelastosis, detected by histology, after a total dose of about 3.5 J/cm²; this was confirmed in measurements of elastin in whole skin by meansof a radioimmunoassay for desmosine. Demosine is found in elastinhydrolysates and is derived from crosslinks in the elastin molecule; itis a reliable index of total elastin. Typically, desmosine increased byabout 2-3 fold after 3.5 J/cm² of UVB irradiation. To effect repair ofthe dermal damage, the UVB irradiation was discontinued and animals weretreated three times per week with various concentrations of thecompounds of formula I dissolved in acetone. Solutions were made upfreshly every week at concentrations such that the dose was delivered in100 μl acetone and applied topically to an area of about 10 cm² on theback of the animal with a plastic pipette; a control group treated withacetone alone was also included.

After 10 weeks of treatment the animals were sacrificed, skin sampleswere taken and processed by standard methods. A six micron section fromeach animal was stained for elastin with Luna's stain and the degree ofrepair measured quantitatively. In this model, repair is defined by theappearance of a normalized dermis extending from the epidermis down tothe layer of compressed elastin. The extent of repair was reflected bythe width of this zone. In these studies, the area of the zone on astandard length of histological section was measured by an imageanalyzer and the results are given as total area in mm² per twentymicroscopic fields. Data was analyzed by Student's t-test. The resultsare given in Table I. In Table I, and Table II each group dosed at aparticular concentration of compound of formula I contained six to tenanimals.

                  TABLE I                                                         ______________________________________                                        Group               Repair Zone, mm.sup.2                                     Control             0.005 ± 0.0001                                         0.1μg of Compound A                                                                            0.017 ± 0.007                                          0.5μg of Compound A                                                                            0.021 ± 0.005*                                         2μg of Compound A                                                                              0.027 ± 0.005**                                        10μg of Compound A                                                                             0.028 ± 0.003***                                       50μg of Compound A                                                                             0.014 ± 0.005                                          Group               Repair Zone                                               Control             0.008 ± 0.003                                          0.1μg of Compound B                                                                            0.012 ± 0.003                                          0.5μg of Compound B                                                                            0.012 ± 0.003                                          2μg of Compound B                                                                              0.018 ± 0.004*                                         10μg of Compound B                                                                             0.025 ± 0.005*                                         50μg of Compound B                                                                             0.020 ± 0.004*                                         Group               Repair Zone, mm.sup.2                                     Control             0.009 ± 0.003                                          0.1μg of Compound C                                                                            0.009 ± 0.002                                          0.5μg of Compound C                                                                            0.033 ± 0.008**                                        2μg of Compound C                                                                              0.038 ± 0.008**                                        10μg of Compound C                                                                             0.043 ± 0.005***                                       50μg of Compound C                                                                             0.039 ± 0.008**                                        ______________________________________                                         *P < 0.05, **P < 0.01, ***P < 0.001 vs Control                           

Throughout the specification,

Compound A is methylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfoxide.

Compound B is ethylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfoxide.

Compound C is ethylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfinate.

EXAMPLE 2 Effect of Compounds of Formula I on the Wrinkles Produced inHairless Mice by UVB-Irradiation

Doses of UVB-irradiation sufficient to induce dermal damage in hairlessmice were found to cause the appearance of wrinkles on the exposed skin.One skin replica for each animal was taken of these areas using a liquiddental impression material (SILFLO-Flexico Developments Ltd., England).Wrinkles appeared in these impressions as ridges which cast a shadowwhen illuminated with low angle light. A characteristic of the wrinklingpattern was the occurrence of the ridges in a regularly-spaced arrayabout 2-mm apart. The extent of wrinkling was visually assessed usingthis line pattern and assigned a value (Wrinkle Index) of zero to 4 withzero representing complete effacement of wrinkling and 4 representingthe maximum degree of wrinkling. It was observed that compounds offormula I caused a dose-dependent effacement of the wrinkles with ED₅₀values in the microgram range. The results are shown in the followingTable.

                  TABLE II                                                        ______________________________________                                        Group                Wrinkle Index                                            Control              1.3 ± 0.2                                             0.1μg of Compound A                                                                             1.3 ± 0.3                                             0.3μg of Compound A                                                                             0.7 ± 0.2*                                            1μg of Compound A 0.3 ± 0.1***                                          3μg of Compound A 0.2 ± 0.1***                                          Group                Wrinkle Index                                            Control              2.6 ± 0.3                                             0.1μg of Compound B                                                                             3.1 ± 0.5                                             0.5μg of Compound B                                                                             2.2 ± 0.5                                             2μg of Compound B 1.8 ± 0.5                                             10μg of Compound B                                                                              1.1 ± 0.3**                                           50μg of Compound B                                                                                   0***                                                Group                Wrinkle Index                                            Control              2.6 ± 0.2                                             0.1μg of Compound C                                                                             2.4 ± 0.2                                             0.5μg of Compound C                                                                             1.3 ± 0.3**                                           2μg of Compound C 0.9 ± 0.3***                                          10μg of Compound C                                                                              0.3 ± 0.1***                                          50μg of Compound C                                                                              0.1 ± 0.1***                                          ______________________________________                                         *P < 0.05, **P < 0.01, ***P < 0.001 vs Control                           

Creams and gels containing ingredients within the proportions set forthin Examples 3 through 7 below can be formulated by conventional means.

EXAMPLE 3

    ______________________________________                                        CREAM                                                                                               % w/w                                                   ______________________________________                                        Compound A              0.00001-1.3                                           Cetyl Alcohol           1.5                                                   Stearyl Alcohol         2.5                                                   Span 60 (Sorbitan Stearate)                                                                           2.0                                                   Mineral Oil             2.0                                                   Arlacel 165 (Glyceryl/PEG 100 Stearate)                                                               4.0                                                   Tween 60 (Polysorbate 80)                                                                             1.0                                                   Miglyol 818 (Caprylic/Capric/Linoleic                                                                 5.0                                                   triglyceride)                                                                 Sorbitol Solution       4.0                                                   Disodium Edetate        0.1                                                   BHA (Butylated Hydroxyanisole)                                                                         0.05                                                 Methylparaben            0.18                                                 Propylparaben            0.05                                                 Water q.s.              100.00                                                ______________________________________                                    

EXAMPLE 4

    ______________________________________                                        CREAM                                                                                             % w/w                                                     ______________________________________                                        A Compound of Formula I                                                                             0.00001-1.0                                             Cetyl Alcohol         5.25-8.75                                               Arlacel 165 (Glyceryl/PEG 100 Stearate)                                                             3.75-6.25                                               Miglyol 818 (Caprylic/Capric/Linoleic                                                               11.25-18.75                                             triglyceride)                                                                 Sorbitol Solution     3.75-6.25                                               Disodium Edetate       .075-0.125                                             Carbopol 934P (Carbomer 934P)                                                                       0.15-0.25                                               BHA (Butylated Hydroxyanisole)                                                                      0.0375-0.0625                                           Methylparaben         0.135-0.225                                             Propylparaben         0.0375-0.0625                                           Sodium Hydroxide (10% solution)                                                                     0.15-0.25                                               Distilled Water, q.s. 100.00                                                  ______________________________________                                    

EXAMPLE 5

    ______________________________________                                        CREAM                                                                                               % w/w                                                   ______________________________________                                        A Compound of Formula I 0.00001-1.0                                           Cutina MD (Glyceryl Stearate)                                                                         4.5-7.5                                               Ceteareth-12            3.0-5.0                                               Cetyl Alcohol           3.0-5.0                                               Generol 122E-10 (Ethoxylated Soya Sterol)                                                             2.25-3.75                                             Cetiol LC (Oleic Acid Decyl Ester)                                                                     7.5-12.5                                             BHA (Butylated Hydroxyanisole)                                                                        0.0375-0.0625                                         Sorbitol Solution       3.75-6.25                                             Disodium Edetate        0.075-0.125                                           Methylparaben           0.135-0.225                                           Propylparaben           0.0375-0.0625                                         Distilled Water, q.s.   100.00                                                ______________________________________                                    

EXAMPLE 6

    ______________________________________                                        CREAM                                                                                             % w/w                                                     ______________________________________                                        Compound A            0.00001-1.0                                             Arlatone 983 (PEG 30/Glyceryl Stearate)                                                             7.0                                                     Cetyl Alcohol         1.0                                                     Stearic Acid          4.0                                                     Neobee Oil (Medium chain-length                                                                     17.0                                                    triglyceride)                                                                 Propylene Glycol      5.0                                                     2-phenoxyethanol      0.5                                                     Distilled Water, q.s  100.00                                                  ______________________________________                                    

EXAMPLE 7

    ______________________________________                                        GEL                                                                                               % w/w                                                     ______________________________________                                        Compound A            0.00001-1.0                                             Pluronic L 101 (Poloxamer 331)                                                                      10.00                                                   Aerosil 200 (Silica)   8.00                                                   PCL Liquid (Fatty Acid Esters)                                                                      15.00                                                   Cetiol V (Decyl Oleate)                                                                             20.00                                                   Neobee Oil (Medium chain-length                                                                     15.00                                                   triglyceride)                                                                 Euhanol G (Octyldodecanol), q.s.                                                                    100.00                                                  ______________________________________                                    

It is understood that the proportions of excipients in creams ofExamples 3 and 6, and the gels of Example 7 can be varied, if desired,to change the physical properties of the resulting creams and gels.

We claim:
 1. A method of treating the conditions associated withphotodamaged skin comprising topically administering a compound of theformula ##STR4## wherein n represents 1 or 2; Z represents --S(O)R,wherein R represents lower-alkyl, lower-alkenyl, lower-alkynyllower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl,hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl,lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino,ora pharmaceutically acceptable salt thereof to an area of the skin inneed of said treatment, said compound of formula I being applied to saidarea in an amount effective to reverse the effects of photodamage insaid area.
 2. A method according to claim 1 wherein R is lower alkyl. 3.A method according to claim 2 wherein the compound of formula I ismethylp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfoxide.4. The method of claim 1 wherein the compound of formula I isadministered in a topical composition containing at least 0.00001% byweight of said compound of formula I and an inert dermatologicallyacceptable carrier.
 5. The method of claim 4, wherein said topicalcomposition contains a compound of formula I in an amount of from about0.00001% to about 1.0% by weight of the composition.
 6. The method ofclaim 5, wherein said topical composition contains a compound of formulaI in amount of from about 0.0001 to about 0.1% by weight of thecomposition.
 7. The method of claim 5, wherein said composition containsa cosmetically active ingredient.
 8. The method of claim 7 wherein saidcosmetically active ingredient is a sunscreen.
 9. The method of claim 4,wherein said composition is a gel, cream or ointment.
 10. The method ofclaim 4, wherein said composition is applied to the face.